Porous celecoxib matrices and methods of manufacture thereof

ABSTRACT

Celecoxib is provided in a porous matrix form wherein the dissolution rate of the drug is enhanced when the matrix is contacted with an aqueous medium. The porous matrix yields upon contact with an aqueous medium nanoparticles and microparticles of celecoxib having a mean diameter between about 0.01 and 5 μm and a total surface area greater than about 0.5 m 2 /mL. The dry porous matrix preferably is in a dry powder form having a TAP density less than or equal to 1.0 g/mL. The porous celecoxib matrices preferably are made using a process that includes (i) dissolving celecoxib in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the dry porous matrix of celecoxib. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug.

[0001] This application claims priority to U.S. Ser. No. 60/211,723,filed Jun. 15, 2000.

BACKGROUND OF THE INVENTION

[0002] This invention generally relates to formulations of the drugcelecoxib, and more particularly to methods of making formulations ofsuch celecoxib to enhance its rate of dissolution.

[0003] The bioavailability of a drug, such as celecoxib, can be limitedby poor dissolution of the drug into aqueous bodily fluids followingadministration. This rate-limiting step may therefore be critical torapidly attaining therapeutically effective drug levels.

[0004] Traditional approaches to parenteral delivery of poorly solubledrugs include using large volumes of aqueous diluents, solubilizingagents, detergents, non-aqueous solvents, or non-physiological pHsolutions. These formulations, however, can increase the systemictoxicity of the drug composition or damage body tissues at the site ofadministration.

[0005] Celecoxib, which is used for example in the treatment ofinflammation of and inflammatory disorders, has some patient relateddrawbacks. These stem, in part, from its extremely low solubility inwater, which makes it difficult to provide in suitable dosage form.There remains a need to develop improved formulations of the celecoxibwhich can be administered with improved oral bioavailability or, forexample, as bolus injections.

[0006] Other approaches to delivery of poorly soluble drugs have focusedon the physical form of the drug itself. Since the dissolution rate of adrug particle is directly related to its surface area available tocontact the aqueous media at the site of administration or site ofabsorption, methods of preparing drugs in nanoparticulate form have beendeveloped in an effort to maximize the drug surface area, as described,for example, in U.S. Pat. No. 5,534,270 to De Castro and U.S. Pat. No.5,587,143 to Wong. Nanoparticles, however, can be difficult to produceand maintain in a stable form due to the tendency of the nanoparticlesto flocculate or agglomerate, particularly without the presence ofsurface modifying agents adsorbed or coated onto the particles.Furthermore, milling or wet grinding techniques, which are typicallyemployed for nanonization, can be undesirable, as it can take severaldays to process a single batch, scaling-up of the milling or grindingprocess can be difficult and/or costly, the process can be difficult toconduct aseptically, and it is difficult to eliminate shedding ofmilling media into the product.

[0007] Other efforts directed at enhancing the rate of dissolution havefocused on delivering the drug as a dispersion in a water-soluble orbiodegradable matrix, typically in the form of polymeric microparticles.For example, the dissolution rate of dexamethasone reportedly wasimproved by entrapping the drug in chitosan microspheres made byspray-drying (Genta, et al., S.T.P. Pharma Sciences 5(3):202-07 (1995)).Similarly, others have reported enhanced dissolution rates by mixing apoorly soluble drug powder with a water-soluble gelatin, whichpurportedly makes the surface of the drug hydrophilic (Imai, et al., J.Pharm. Pharmacol., 42:615-19 (1990)).

[0008] Related efforts have been directed to forming relatively large,porous matrices of low solubility drugs. For example, Roland &Paeratakul, “Spherical Agglomerates of Water-Insoluble Drugs,” J.Pharma. Sci., 78(11):964-67 (1989) discloses preparing beads having alow solubility drug content up to 98%, wherein the beads have a porousinternal structure. Such large beads, however, are unsuitable forparenteral administration, and the beads have less surface area andslower dissolution rates than smaller particles.

[0009] It is therefore an object of the present invention to providecompositions enhancing the dissolution rate of low aqueous solubilitydrugs, particularly celecoxib, and to provide methods of making suchcompositions.

[0010] It is another object of the present invention to providecelecoxib compositions in a formulation suitable for administration by avariety of routes, including, but not limited to, parenteral, mucosal,oral, and topical administration, for local, regional, or systemiceffect.

[0011] It is another object of the present invention to providecompositions providing enhanced dissolution of celecoxib in aformulation suitable for administration by a variety of routes,including, but not limited to, parenteral, mucosal, oral, and topicaladministration, for local, regional, or systemic effect.

SUMMARY OF THE INVENTION

[0012] Celecoxib is provided in a porous matrix form wherein thedissolution rate of the drug is enhanced when the matrix is contactedwith an aqueous medium. The porous matrix yields upon contact with anaqueous medium nanoparticles and microparticles of celecoxib having amean diameter between about 0.01 and 5 μm and a total surface areagreater than about 0.5 m²/mL. The dry porous matrix preferably is in adry powder form having a TAP density less than or equal to 1.0 g/mL.

[0013] The porous matrices that contain the celecoxib preferably aremade using a process that includes (i) dissolving celecoxib in avolatile solvent to form a drug solution, (ii) combining at least onepore forming agent with the drug solution to form an emulsion,suspension, or second solution, and (iii) removing the volatile solventand pore forming agent from the emulsion, suspension, or second solutionto yield the dry porous matrix of celecoxib. The resulting porous matrixhas a faster rate of dissolution following administration to a patient,as compared to non-porous matrix forms of the drug. The pore formingagent can be either a volatile liquid that is immiscible with the drugsolvent or a volatile solid compound, preferably a volatile salt. If thepore forming agent is a liquid, the agent is emulsified with the drugsolution. If the pore forming agent is a solid, the agent is (i)dissolved in the drug solution, (ii) dissolved in a solvent that is notmiscible in the drug solvent and then emulsified with the drug solution,or (iii) suspended as solid particulates in the drug solution.Optionally, hydrophilic excipients, wetting agents, and/or tonicityagents may be added to the drug solvent, the pore forming agent solvent,or both. The solution, emulsion, or suspension of the pore forming agentin the drug solution is then processed to remove the drug solvent andthe pore forming agent, as well as any pore forming agent solvent. In apreferred embodiment, spray drying, optionally followed bylyophilization, fluid bed drying, or vacuum drying, is used to removethe solvents and the pore forming agent.

[0014] In a preferred embodiment, the porous celecoxib matrix is furtherprocessed using standard techniques into tablets or capsules for oraladministration or into rectal suppositories, delivered using a drypowder inhaler for pulmonary administration, or mixed/processed into acream or ointment for topical administrationt. Alternatively, the porouscelecoxib matrix is reconstituted with an aqueous medium andadministered parenterally, such as intramuscularly, subcutaneously, orintravenously.

[0015] An advantage of the porous drug matrix formulations is that theycan be administered as a bolus, when the drug normally must be infusedto avoid precipitation of the drug. By avoiding precipitation of drug invivo, the formulations can also be administered intrarterially,intravenously, locally, intracranially, or intrathecally. An additionaladvantage is the formulations can be administered in reduced volumes.

[0016] In one embodiment, the matrix further includes a pegylatedexcipient, such as pegylated phospholipid, with the celecoxib. Thepegylated excipient shields the drug from macrophage uptake, whichprolong its half-life or enhance bioavailability of the drug.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 is a graph of the in vitro dissolution rate (percentdissolved versus time) for non-formulated celecoxib and celecoxib inporous matrix form.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The rate of dissolution of celecoxib can be enhanced by makingthe drug into a porous matrix form, substantially increasing the surfacearea of the drug available to contact aqueous biological fluids at thesite of administration of the drug composition. The method for makingthe porous matrix of drug includes the steps of (a) dissolving celecoxibin a volatile solvent to form a drug solution, (b) combining at leastone pore forming agent with the drug solution to form an emulsion,suspension, or second solution, and (c) removing the volatile solventand pore forming agent from the emulsion, suspension, or second solutionto yield the porous matrix of celecoxib. In a preferred embodiment, thecelecoxib compositions are porous dry powders, which upon the additionof an aqueous medium form a suspension of nanoparticles andmicroparticles of the drug.

I. Drug Matrix Compositions

[0019] The porous drug matrix is at least 1 to 95%, preferably at leastabout 10%, and more preferably between about 10 and 70%, celecoxib byweight. The matrices also may contain hydrophilic excipients such aswater soluble polymers or sugars, wetting agents such as surfactants,and tonicity agents.

[0020] The form of the drug matrix (drug powder) is critical to thedissolution rate of the celecoxib. The matrix must containmicroparticles of drug, which preferably have a mean diameter betweenabout 0.01 and 5 μm, more preferably between about 0.1 and 5 μm. In oneembodiment, the mean diameter of the microparticles is between about 0.5and 5 μm. The average total surface area of the microparticles containedwithin the porous matrix, which typically is in the form of a drypowder, is 0.5 m²/mL or greater, preferably 0.9 m²/mL or greater. Totalsurface area values for the microparticles can be determined usingstandard Coulter Counter equipment and techniques.

[0021] The celecoxib matrix must be sufficiently porous to yield, uponcontact with an aqueous medium, microparticles having these parameters.Measurements useful in characterizing the porosity of the drug matrixare the bulk density or the transaxial pressure (“TAP”) density of thedry porous matrix (dry powder) and the total surface area (sum ofinternal and external surface area) of the dry porous matrix. The TAPdensity preferably is less than or equal to 1.0 g/ml, more preferablyless than 0.8 g/ml. This level of porosity of the matrix, characterizedby density, provides sufficient surface area to enhance wetting of thedry porous matrix and enhance drug dissolution. The total surface areaof the porous matrix can be measured, for example, by BET surface areaanalysis. In some embodiments, the total surface area of the porousmatrix preferably is greater than 0.1 m²/g, more preferably greater thanor equal to 0.2 m²/g. This level of total surface area providessufficient surface area to enhance wetting of the dry porous matrix andenhance drug dissolution.

The Drug Celecoxib

[0022] Celecoxib is a nonsteroidal anti-inflammatory drug that exhibitsantinflammatory, analgesic and antipyretic effects. The mechanism ofaction is believed to be due to inhibition of prostaglandin synthesis,primarily via inhibition of cyclooxygenase-2 (COX-2). The drug iscurrently used for the treatment of osteoarthritis and rheumatoidarthritis.

[0023] As used herein, the term “low aqueous solubility” means that thedrug has a solubility of less than about 10 mg/mL, and preferably lessthan about 5 mg/mL, in aqueous media at approximately physiologicaltemperatures and pH. As used herein, the term “drug” is usedinterchangeably with “celecoxib” unless otherwise indicated.

Excipients

[0024] The matrices may contain hydrophilic excipients such as watersoluble polymers or sugars which can serve as bulking agents or aswetting agents, wetting agents such as surfactants or sugars, andtonicity agents. Upon contact with an aqueous medium, water penetratesthrough the highly porous matrix to dissolve the water solubleexcipients in the matrix. In the case of low aqueous solubility drugs, asuspension of drug particles in the aqueous medium remains. The totalsurface area of the resultant low aqueous solubility drug microparticlesis increased relative to the unprocessed drug and the dissolution rateof the drug is increased.

[0025] One of skill in the art can select appropriate excipients for usein the drug matrix compositions, considering a variety of factors, suchas the drug to be administered, the route of administration, the dosage,and the preferred dissolution rate. For example, the excipients canfunction as bulking agents, release-modifiers, wetting agents, tonicityagents, or combinations thereof. Preferred excipients includehydrophilic polymers, wetting agents, and sugars. The amount ofexcipient in the drug matrix is less than about 95%, more preferablyless than about 80%, by weight of the drug matrix.

[0026] The hydrophilic excipients, wetting agents, and tonicity agentsmay be added to the drug solution, the pore forming agent, or both,during production of the matrix.

Hydrophilic Polymers

[0027] The polymers that can be used in the drug matrices describedherein include both synthetic and natural polymers, eithernon-biodegradable or biodegradable. Representative synthetic polymersinclude polyethylene glycol (“PEG”), polyvinyl pyrrolidone,polymethacrylates, polylysine, poloxamers, polyvinyl alcohol,polyacrylic acid, polyethylene oxide, and polyethyoxazoline.Representative natural polymers include albumin, alginate, gelatin,acacia, chitosan, cellulose dextran, ficoll, starch, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxy-propylmethyl cellulose,hyaluronic acid, carboxyethyl cellulose, carboxymethyl cellulose,deacetylated chitosan, dextran sulfate, and derivatives thereof.Preferred hydrophilic polymers include PEG, polyvinyl pyrrolidone,poloxamers, hydroxypropyl cellulose, and hydroxyethyl cellulose.

[0028] The hydrophilic polymer selected for use in a particular drugmatrix formulation is based on a variety of factors, such as the polymermolecular weight, polymer hydrophilicity, and polymer inherentviscosity. The hydrophilic polymer can be used as a bulking agent or asa wetting agent.

(ii) Sugars

[0029] Representative sugars that can be used in the drug matricesinclude mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol,arabinitol, arabitol, galactitol, iditol, allitol, fructose, sorbose,glucose, xylose, trehalose, allose, dextrose, altrose, gulose, idose,galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose,lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, andraffinose. Preferred sugars include mannitol, lactose, sucrose,sorbitol, trehalose, glucose, and are adjusted to provide osmolality ifadministered parenterally or to provide wetting of the porous drugmatrix or the drug microparticles within the matrix.

Wetting Agents

[0030] Wetting agents can be used to facilitate water ingress into thematrix and wetting of the drug particles in order to facilitatedissolution. Representative examples of wetting agents include gelatin,casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth,stearic acid, benzalkonium chloride, calcium stearate, glycerolmonostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol etherssuch as cetomacrogol 1000), polyoxyethylene castor oil derivatives,polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN™s), polyethyleneglycols, polyoxyethylene stearates, colloidal silicon dioxide,phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxy propylcellulose, hydroxypropylmethylcellulose phthlate,noncrystalline cellulose, magnesium aluminum silicate, triethanolamine,polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionicliquid polymer of the alkyl aryl polyether alcohol type, also known assuperinone or triton) is another useful wetting agent. Most of thesewetting agents are known pharmaceutical excipients and are described indetail in the Handbook of Pharmaceutical Excipients, published jointlyby the American Pharmaceutical Association and The PharmaceuticalSociety of Great Britain (The Pharmaceutical Press, 1986).

[0031] Preferred wetting agents include polyvinylpyrrolidone,polyethylene glycol, tyloxapol, poloxamers such as PLURONIC™ F68, F127,and F108, which are block copolymers of ethylene oxide and propyleneoxide, and polyxamines such as TETRONIC™ 908 (also known as POLOXAMINE™908), which is a tetrafunctional block copolymer derived from sequentialaddition of propylene oxide and ethylene oxide to ethylenediamine(available from BASF), dextran, lecithin, dialkylesters of sodiumsulfosuccinic acid such as AEROSOL™ 80, which is a dioctyl ester ofsodium sulfosuccinic acid (available from American Cyanimid), DUPONOL™P, which is a sodium lauryl sulfate (available from DuPont), TRITON™X-200, which is an alkyl aryl polyether sulfonate (available from Rohmand Haas), TWEEN™ 20 and TWEEN™ 80, which are polyoxyethylene sorbitanfatty acid esters (available from ICI Specialty Chemicals), Carbowax3550 and 934, which are polyethylene glycols (available from UnionCarbide), Crodesta F-110, which is a mixture of sucrose stearate andsucrose distearate, and Crodesta SL-40 (both available from Croda Inc.),and SA90HCO, which is C₁₈H₃₇CH₂(CON(CH₃)CH₂(CHOH)₄CH₂OH)₂.

[0032] Wetting agents which have been found to be particularly usefulinclude Tetronic 908, the Tweens, Pluronic F-68 andpolyvinylpyrrolidone. Other useful wetting agents includedecanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside;n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside;n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide;n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; and octyl-β-D-thioglucopyranoside. Anotherpreferred wetting agent is p-isononylphenoxypoly(glycidol), also knownas Olin-10G or Surfactant 10-G (commercially available as 10G from OlinChemicals). Two or more wetting agents can be used in combination.

Tonicity or Osmolality Agents

[0033] The porous drug matrices may include one or more tonicity agents,such as salts (e.g., as sodium chloride or potassium chloride) or sugars(such as mannitol, dextrose, sucrose, or trehalose) to adjust ahypotonic solution of a drug to isotonic so that the drug, when insolution, is physiologically compatible with the cells of the bodytissue of the patient. The type and amount of tonicity agent can beselected by one of skill in the art using known techniques.

Pegylated Excipients

[0034] In one embodiment, the matrix further includes a pegylatedexcipient. Such pegylated excipients include, but are not limited to,pegylated phospholipids, pegylated proteins, pegylated peptides,pegylated sugars, pegylated polysaccharides, pegylated block copolymerswith one of the blocks being PEG, and pegylated hydrophobic compoundssuch as pegylated cholesterol. The pegylated excipient beneficiallyenvelops or shields the drug from macrophage uptake, which prolongs itshalf-life or enhances bioavailability of the drug.

[0035] Representative examples of pegylated phospholipids include1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethyleneglycol)2000](“PEG 2000 PE”) and1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol)5000](“PEG 5000 PE”), where the acyl group is selected, for example,from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and1-palmitoyl-2-oleoyl.

[0036] Other polyalkyleneoxides can be used in place of thepolyethylene.

II. Volatile Solvents

[0037] In a preferred embodiment, the solvent is an organic solvent thatis volatile, has a relatively low boiling point, or can be removed undervacuum, and which is acceptable for administration to humans in traceamounts. Representative solvents include acetic acid, acetaldehydedimethyl acetal, acetone, acetonitrile, chloroform, chlorofluorocarbons,dichloromethane, dipropyl ether, diisopropyl ether,N,N-dimethlyformamide (DMF), foramide, demethyl sulfoxide (DMSO),dioxane, ethanol, ethyl acetate, ethyl formate, ethyl vinyl ether,methyl ethyl ketone (MEK), glycerol, heptane, hexane, isopropanol,methanol, isopropanol, butanol, triethylamine, nitromethane, octane,pentane, tetrahydrofuran (THF), toluene, 1,1,1-trichloroethane,1,1,2-trichloroethylene, water, xylene, and combinations thereof. Ingeneral, the drug is dissolved in the volatile solvent to form a drugsolution having a concentration of between 0.01 and 80% weight to volume(w/v), more preferably between 0.025 and 30% (w/v).

[0038] Aqueous solvents or mixtures of aqueous and organic solvents,such as water-alcohol mixtures, can be used to dissolve the celecoxib.

III. Pore Forming Agents

[0039] Pore forming agents are volatile materials that are used duringthe process to create porosity in the resultant matrix. The pore formingagent can be a volatilizable solid or volatilizable liquid.

Liquid Pore Forming Agent

[0040] The liquid pore forming agent must be immiscible with the drugsolvent and volatilizable under processing conditions compatible withthe drug. To effect pore formation, the pore forming agent first isemulsified with the drug solvent. Then, the emulsion is furtherprocessed to remove the drug solvent and the pore forming agentsimultaneously or sequentially using evaporation, vacuum drying, spraydrying, fluid bed drying, lyophilization, or a combination of thesetechniques.

[0041] The selection of liquid pore forming agents will depend on thedrug solvent. Representative liquid pore forming agents include water;dichloromethane; alcohols such as ethanol, methanol, or isopropanol;acetone; ethyl acetate; ethyl formate; dimethylsulfoxide; acetonitrile;toluene; xylene; dimethylforamide; ethers such as THF, diethyl ether, ordioxane; triethylamine; foramide; acetic acid; methyl ethyl ketone;pyridine; hexane; pentane; furan; water; and cyclohexane.

[0042] The liquid pore forming agent is used in an amount that isbetween 1 and 50% (v/v), preferably between 5 and 25% (v/v), of the drugsolvent emulsion.

Solid Pore Forming Agent

[0043] The solid pore forming agent must be volatilizable underprocessing conditions which do not harm the drug compositions. The solidpore forming agent can be (i) dissolved in the drug solution, (ii)dissolved in a solvent which is not miscible with the drug solvent toform a solution which is then emulsified with the drug solution, or(iii) added as solid particulates to the drug solution. The solution,emulsion, or suspension of the pore forming agent in the drug solutionthen is further processed to remove the drug solvent, the pore formingagent, and, if appropriate, the solvent for the pore forming agentsimultaneously or sequentially using evaporation, spray drying, fluidbed drying, lyophilization, vacuum drying, or a combination of thesetechniques.

[0044] In a preferred embodiment, the solid pore forming agent is avolatile salt, such as salts of volatile bases combined with volatileacids. Volatile salts are materials that can transform from a solid orliquid to a gaseous state using added heat and/or vacuum. Examples ofvolatile bases include ammonia, methylamine, ethylamine, dimethylamine,diethylamine, methylethylamine, trimethylamine, triethylamine, andpyridine. Examples of volatile acids include carbonic acid, hydrochloricacid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid,propionic acid, butyric acid, and benzoic acid. Preferred volatile saltsinclude ammonium bicarbonate, ammonium acetate, ammonium chloride,ammonium benzoate and mixtures thereof.

[0045] Other examples of solid pore forming agents include iodine,phenol, benzoic acid (as acid not as salt), and naphthalene.

[0046] The solid pore forming agent is used in an amount between 0.5 and1000% (w/w), preferably between 10 and 600% (w/w), and more preferablybetween 1 and 100% (w/w), of the drug.

IV. Method of Making the Porous Drug Matrix

[0047] The porous drug matrices preferably are made by (i) dissolvingthe celecoxib in a volatile solvent to form a drug solution, (ii)combining at least one pore forming agent with the drug solution to forman emulsion, suspension, or second solution, and (iii) removing thevolatile solvent and pore forming agent from the emulsion, suspension,or second solution. In a preferred embodiment, spray drying, optionallyfollowed by lyophilization or vacuum drying, is used to remove thesolvents and the pore forming agent. The removal of the pore formingagent can be conducted simultaneously with or following removal ofenough solvent to solidify the droplets. Production can be carried outusing continuous, batch, or semi-continuous processes.

[0048] First, the celecoxib is dissolved in an appropriate solvent. Theconcentration of the drug in the resulting drug solution typically isbetween about 0.01 and 80% (w/v), preferably between about 0.025 and 30%(w/v).

[0049] Next, the drug solution is combined, typically under mixingconditions, with the pore forming agent or solution thereof. If a liquidpore forming agent is used, it is first emulsified with the drugsolution to form droplets of pore forming agent dispersed throughout thedrug solution. If a solid pore forming agent is used, it is dissolvedeither directly in the drug solution to form a solution of drug/poreforming agent, or it is first dissolved in a second solvent. If thesecond solvent is immiscible with the drug solvent, the solution of thepore forming agent is emulsified with the drug solution to form dropletsof the pore forming agent solution dispersed throughout the drugsolution. If the second solvent is miscible with the drug solution, thetwo solutions are mixed to form a single drug solution. A solid poreforming agent alternatively can be added directly to the drug solutionas solid particulates, preferably between about 100 nm and 10 μm insize, to form a suspension of pore forming agent in the drug solution.Subsequently, the solid pore forming agent particle size can be reducedby further processing the resulting suspension, for example, usinghomogenization or sonication techniques known in the art.

[0050] Then, the solution, emulsion, or suspension is further processedto remove the drug solvent and the pore forming agent simultaneously orsequentially, using evaporation, spray drying, fluid bed drying,lyophilization, vacuum drying, or a combination of these techniques. Ina preferred embodiment, the solution, emulsion, or suspension isspray-dried. As used herein, “spray dry” means to atomize the solution,emulsion, or suspension to form a fine mist of droplets (of drugsolution having solid or liquid pore forming agent dispersedthroughout), which immediately enter a drying chamber (e.g., a vessel,tank, tubing, or coil) where they contact a drying gas. The solvent andpore forming agents evaporate from the droplets into the drying gas tosolidify the droplets, simultaneously forming pores throughout thesolid. The solid (typically in a powder, particulate form) then isseparated from the drying gas and collected.

[0051] The temperature of the inlet and outlet ports of the dryingchamber, as well as the flow rates of the feed solution, atomizationgas, and drying gas, can be controlled to produce the desired products.In a particularly preferred embodiment, the spray drying methodsdescribed in U.S. Pat. No. 5,853,698 to Straub et al. are adapted tomake the drug matrices.

[0052] The drug present in the solids or powder produced may be in acrystalline or an amorphous state, or may be mixture of such states. Thestate generally depends on how the droplets are dried and the excipientspresent.

Emulsion Stabilization

[0053] In embodiments in which at least one pore forming agent iscombined with the drug solution to form an emulsion, a surfactant oremulsifying agent can be added to enhance the stability of the emulsion.A variety of surfactants may be incorporated in this process, preferablyto an amount between 0.1 and 5% by weight. Exemplary emulsifiers orsurfactants which may be used include most physiologically acceptableemulsifiers, for instance egg lecithin or soya bean lecithin, orsynthetic lecithins such as saturated synthetic lecithins, for example,dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline ordistearoyl phosphatidyl choline or unsaturated synthetic lecithins, suchas dioleyl phosphatidyl choline or dilinoleyl phosphatidyl choline.Other hydrophobic or amphipathic compounds can be used in place of thephospholipid, for example, cholesterol. Emulsifiers also includesurfactants such as free fatty acids, esters of fatty acids withpolyoxyalkylene compounds like polyoxpropylene glycol andpolyoxyethylene glycol; ethers of fatty alcohols with polyoxyalkyleneglycols; esters of fatty acids with polyoxyalkylated sorbitan; soaps;glycerol-polyalkylene stearate; glycerol-polyoxyethylene ricinoleate;homo- and co-polymers of polyalkylene glycols; polyethoxylated soya-oiland castor oil as well as hydrogenated derivatives; ethers and esters ofsucrose or other carbohydrates with fatty acids, fatty alcohols, thesebeing optionally polyoxyalkylated; mono-, di- and tri-glycerides ofsaturated or unsaturated fatty acids, glycerides of soya-oil andsucrose.

[0054] Other emulsifiers include natural and synthetic forms of bilesalts or bile acids, both conjugated with amino acids and unconjugatedsuch as taurodeoxycholate and cholic acid.

V. Porous Drug Matrix Applications

[0055] The porous celecoxib matrices described herein are useful informulations for administration to a patient in need of the drug. Asused herein, “patient” refers to animals, including mammals, preferablyhumans. The formulations deliver a therapeutically or prophylacticallyeffective amount of the drug to the patient.

[0056] The celecoxib formulations described herein are useful, forexample, as anti-inflammatory, analgesic, and antipyretic therapeuticagents. The drug is currently used for the treatment of osteoarthritisand rheumatoid arthritis. Other treatments using celecoxib aredescribed, for example, in U.S. Pat. No. 6,046,191, which isincorporated by reference.

[0057] The porous matrices, or formulations thereof, are suitable foradministration of celecoxib by a variety of routes, for example,parenteral, mucosal, oral, topical/transdermal administration, forlocal, regional, or systemic effect. Examples of parenteral routesinclude intraveneous, intraarterial, intracardiac, intrathecal,intraosseous, intraarticular, intrasynovial, intracutaneous,subcutaneous, and intramuscular administration. Examples of mucosalroutes include pulmonary (intrarespiratory), buccal, sublingual,intranasal, rectal, and vaginal administration. The porous matrices alsocan be formulated for intraocular, conjunctival, aural, urethral,intracranial, intralesional, and intratumoral administration.

[0058] In a preferred embodiment, the celecoxib matrix is in the form ofpowder, which can be reconstituted with an aqueous medium, such asphysiological saline, and administered parenterally, such asintramuscularly, subcutaneously, or intravenously. An advantage of theformulations described herein is that they can be used to convert drugswhich must be infused (e.g., to avoid precipitation of the drugfollowing bolus injection) to a bolus formulation, avoiding unacceptableprecipitation of drug in vivo or for local delivery.

[0059] Alternatively, the matrix can be further processed using standardtechniques into tablets or capsules for oral administration, into rectalsuppositories, into a dry powder inhaler for pulmonary administration,or mixed/processed into a cream or ointment for topical administration.These standard techniques are described, for example, in Ansel, et al.,“Pharmaceutical Dosage Forms and Drug Delivery Systems,” 6th Ed.,(Williams & Wilkins 1995).

[0060] The present invention will be further understood with referenceto the following non-limiting examples.

Materials and Equipment Used in the Examples

[0061] The following materials were obtained from Spectrum Chemicals,Gardena, Calif.: sodium dodecyl sulfate (SDS), mannitol, ammoniumbicarbonate, polyvinylpyrrolidone K-30, and ethanol. Celecoxib wasobtained from Cipla Ltd, Mumbai, India. Solutions were mixed using amagnetic stirbar and a digital hotplate/stirrer (model 04644, ColeParmer, Vernon Hills, Ill.). All solutions were spray dried on abenchtop spray dryer using an air-atomizing nozzle. The overhead mixerused for the dissolution studies was an IKA RW16 Basic Mixer with aR1342 propeller shaft.

EXAMPLE 1

[0062] Production of a Porous Celecoxib Matrix

[0063] A celecoxib-loaded organic solution was prepared by dissolving1.0 g of celecoxib and 0.10 g of polyvinylpyrrolidone K-30 in 160 ml ofethanol. An aqueous solution composed of 0.42 g of ammonium bicarbonate,1.0 g of mannitol, and 0.10 g of sodium dodecyl sulfate (SDS) in 40 mlof DI water was added to the ethanol solution and mixed. The resulting80% ethanol solution was spray dried using nitrogen as both theatomizing and drying gas. Spray drying conditions were as follows: 30ml/min solution flow rate, 30 L/min atomization gas rate, 100 kg/hrdrying gas rate, and 30° C. outlet temperature.

EXAMPLE 2

[0064] In vitro Dissolution of a Porous Celecoxib Matrix

[0065] Dissolution studies for celecoxib were conducted in phosphatebuffered saline containing 0.08% Tween 80 (T80/PBS) at room temperaturein a glass beaker using overhead mixing with the stirring rate set to 5.T80/PBS (700 mL) was added to an appropriate amount of material beingtested to contain 2.45 mg of celecoxib. Samples were removed via pipetand filtered through 0.22 μm CA syringe filter. Samples were analyzedvia UV-vis spectroscopy (Hewlett Packard Model 8453) for celecoxib using249 nm. As shown in FIG. 1, the celecoxib from the supplier was 50%dissolved after 1 hour, while the porous celecoxib matrix produced inExample 1, in contrast, was essentially fully dissolved after 10minutes. The data in FIG. 1 is shown as percent of complete dissolution.

[0066] Modifications and variations of the present invention will beobvious to those of skill in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the following claims.

We claim:
 1. A method for making a porous matrix of drug comprising (a)dissolving celecoxib in a volatile solvent to form a drug solution, (b)combining at least one pore forming agent with the drug solution to forman emulsion, suspension, or second solution, and (c) removing thevolatile solvent and pore forming agent from the emulsion, suspension,or second solution to yield the porous matrix of celecoxib.
 2. Themethod of claim 1 further comprising incorporating at least one wettingagent into the emulsion, suspension, or second solution.
 3. The methodof claim 1 wherein step (c) is conducted using a process selected fromspray drying, evaporation, fluid bed drying, lyophilization, vacuumdrying, or a combination thereof.
 4. The method of claim 1 wherein thedrug solution or pore forming agent further comprises an excipientselected from the group consisting of hydrophilic polymers, sugars,pegylated excipients, and tonicity agents.
 5. The method of claim 1wherein the pore forming agent is a volatile salt.
 6. The method ofclaim 6 wherein the volatile salt is selected from the group consistingof ammonium bicarbonate, ammonium acetate, ammonium chloride, ammoniumbenzoate, and mixtures thereof.
 7. The method of claim 1 which yields aporous matrix formed of a wetting agent and microparticles of a drug,wherein the microparticles have a mean diameter between about 0.01 and 5μm and a total surface area greater than about 0.5 m²/mL, and whereinthe porous matrix is in a dry powder form.
 8. A pharmaceuticalcomposition comprising a porous matrix which comprises a wetting agentand microparticles of celecoxib, wherein the microparticles have a meandiameter between about 0.01 and 5 μm and a total surface area greaterthan about 0.5 m²/mL, and wherein the porous matrix has a TAP densityless than or equal to 1.0 g/mL and/or has a total surface area ofgreater than or equal to 0.2 m²/g and is in the form of a dry powder. 9.The composition of claim 8 wherein the dry powder form of the porousmatrix has a TAP density less than or equal to 1.0 g/mL.
 10. Thecomposition of claim 9 wherein the matrix upon contact with an aqueousmedium yields microparticles having a mean diameter between about 0.1and 5 μm and a total surface area greater than about 0.5 m²/mL.
 11. Thecomposition of claim 8 wherein the matrix further comprise an excipientselected from the group consisting of hydrophilic polymers, sugars,tonicity agents, pegylated excipients, and combinations thereof.
 12. Thecomposition of claim 8 wherein the mean diameter of the microparticlesis between about 0.01 and 5 μm.
 13. The composition of claim 12 whereinthe mean diameter of the microparticles is between about 0.5 and 5 μm.14. The composition of claim 13 wherein the mean diameter of themicroparticles is between about 1 and 5 μm.
 15. The composition of claim8 wherein the microparticles are suspended in an aqueous solutionsuitable for parenteral administration.
 16. The composition of claim 8wherein the matrix is processed into tablets or capsules suitable fororal administration.
 17. The composition of claim 8 wherein the matrixis formed into suppositories suitable for vaginal or rectaladministration.
 18. The composition of claim 8 wherein the matrix is ina dry powder form suitable for pulmonary administration.
 19. Thecomposition of claim 8 wherein the porous matrix is made by a processcomprising (a) dissolving celecoxib in a volatile solvent to form a drugsolution, (b) combining at least one pore forming agent with the drugsolution to form an emulsion, suspension, or second solution, (c)incorporating at least one wetting agent into the emulsion, suspension,or second solution, and (d) removing the volatile solvent and poreforming agent from the emulsion, suspension, or second solution to yieldthe porous matrix.
 20. A method of delivering celecoxib to a patient inneed thereof, comprising administering a therapeutically orprophylactically effective amount of celecoxib in a formulationcomprising the composition of any of claims 8-18.
 21. The method ofclaim 20 wherein the formulation is suitable for administration by aroute selected from the group consisting of parenteral, mucosal, oral,and topical administration.
 22. The method of claim 21 wherein theparenteral route is selected from the group consisting of intraveneous,intraarterial, intracardiac, intrathecal, intraosseous, intraarticular,intrasynovial, intracutaneous, subcutaneous, and intramuscularadministration.
 23. The method of claim 21 wherein the mucosal route isselected from the group consisting of pulmonary, buccal, sublingual,intranasal, rectal, and vaginal administration.
 24. The method of claim21 wherein the formulation is suitable for intraocular or conjunctivaladministration.
 25. The method of claim 21 wherein the formulation is inan aqueous solution suitable for parenteral administration.